The retinal pigment epithelium (RPE) is critically involved in many functions required for normal retinal function including the flow of nutrients and waste products between the photoreceptors and the choroidal circulation, the visual cycle, and the phagocytosis of shed outer segment disks. In addition, mutations in RPE-specific genes have been implicated in a wide range of hereditary retinal disease, and this information is being used to develop corresponding mouse models. In the present project, the focus is on the electrical responses generated by the RPE in response to activity of the neural retina. While specific aspects of RPE function may be studied using the electroretinogram (ERG) recorded using dc-coupled amplification, this has not been applied to the mouse. Moreover, fundamental questions remain regarding the origin of the different components of the dc-ERG. In Aim 1, we will study normal wild-type mice, to define the stimulus-response characteristics of the mouse dc-ERG, and the time course over which these develop. In Aim 2, we will test the hypothesis that the mouse dc-ERG is initiated primarily by rod photoreceptor activity, using KO lines for transducin and rhodopsin, and mutants in which the cone population is increased (rd7) or decreased (comas transgenic). In Aim 3, we will use Kir4.1 KO mice to test the hypothesis that this channel is involved in c-wave generation. In Aim 4, we will use cftr KO mice and adenoviral delivery of CFTR constructs to test the hypothesis that the fast oscillation is generated by CFTR activity. In Aim 5, we will use dc-ERG recordings to study the relationship between photoreceptor degeneration and changes in RPE function. First, we will examine how A2E accumulation in abcr-mutant mice alters RPE function. Next, we will test the hypothesis that functional RPE abnormalities occur at early stages using three lines of mice with similar rates of photoreceptor degeneration. In two, the primary defect resides in the photoreceptors (rds/+ and Bouse transgenic mice). In vitilligo mice, a similar rate of photoreceptor degeneration is induced by defect in the RPE. At the completion of this project, we expect to have defined an optimal means for recording the mouse dc-ERG in vivo, to have a thorough understanding of the processes that underlie the different components of the dc-ERG, and a more complete understanding of how these components are affected by disorders of the outer retina.